IMALOTAB

IMALOTAB
Packing3 blister packs of 10 tablets
Shelf life36 months
CompositionImatinib (mesilate form) 400 mg
Posology and pharmaceutical formFilm-coated tablet

Summary of product characteristic

Indications, posology and method of administration

THERAPEUTIC INDICATIONS
Imatinib is indicated for the treatment of:

Adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.
Adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.
Adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
Adult patients with relapsed or refractory Ph+ ALL as monotherapy.
Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
Adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement.

The effect of imatinib on the outcome of bone marrow transplantation has not been determined.

The treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
The adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD 117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
The treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.

In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. Except in newlydiagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.
POSOLOGY AND METHOD OF ADMINISTRATION
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.
The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
Posology for CML in adult patients
The recommended dosage of imatinib is 400 mg/day for adult patients in chronic phase CML. Chronic phase CML is defined when all of the following criteria are met: blasts < 15% in blood and bone marrow, peripheral blood basophils < 20%, platelets > 100 x 109/l.
The recommended dosage of imatinib is 600 mg/day for adult patients in accelerated phase. Accelerated phase is defined by the presence of any of the following: blasts ≥ 15% but < 30% in blood or bone marrow, blasts plus promyelocytes ≥ 30% in blood or bone marrow (providing < 30% blasts), peripheral blood basophils ≥ 20%, platelets < 100 x 109/l unrelated to therapy.
The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.
Dose increases from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.
Posology for CML in children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients. There is no experience with the treatment of children below 2 years of age.
Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.
Posology for Ph+ ALL in adult patients
The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care.
Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy for adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme selected, but generally longer exposures to imatinib have yielded better results.
For adult patients with relapsed or refractory Ph+ ALL imatinib monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs.
Posology for Ph+ ALL in children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg).
Posology for MDS/MPD
The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD.
Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 47 months (24 days – 60 months).
Posology for HES/CEL
The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL.
Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Treatment should be continued as long as the patient continues to benefit.
Posology for GIST
The recommended dose of imatinib is 400 mg/day for adult patients with unresectable and/or metastatic malignant GIST.
Limited data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower dose.
Treatment duration: In clinical trials in GIST patients, treatment with imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months). The effect of stopping treatment after achieving a response has not been investigated.
The recommended dose of imatinib is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 36 months.
Posology for DFSP
The recommended dose of imatinib is 800 mg/day for adult patients with DFSP.
Dose adjustment for adverse reactions
Non-haematological adverse reactions
If a severe non-haematological adverse reaction develops with imatinib use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN.
Treatment with imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day.
Haematological adverse reactions
Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.
Dose adjustments for neutropenia and thrombocytopenia:

HES/CEL (starting dose 100 mg)	ANC < 1.0 x 109/l and/or platelets < 50 x 109/l	1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).
Chronic phase CML, MDS/MPD and GIST (starting dose 400 mg) HES/CEL (at dose 400 mg)	ANC < 1.0 x 109/l and/or platelets < 50 x 109/l	1. Stop imatinib until ANC ≥ 1,5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1,0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume imatinib at reduced dose of 300 mg.
Paediatric chronic phase CML (at dose 340 mg/m2)	ANC < 1.0 x 109/l and/or platelets < 50 x 109/l	1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 x109/l, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2.
Accelerated phase CML and blast crisis and Ph+ ALL (starting dose 600 mg)	aANC < 0.5 x 109/l and/or platelets < 10 x 109/l	1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 300 mg.
Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2)	aANC < 0.5 x 109/l and/or platelets < 10 x 109/l	1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 260 mg/m2. 3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then resume treatment at 200 mg/m2.
DFSP (at dose 800 mg)	ANC < 1.0 x 109/l and/or platelets < 50 x 109/l	1. Stop imatinib until ANC ≥ 1.5 x 109/l and platelets ≥ 75 x 109/l. 2. Resume treatment with imatinib at 600 mg. 3. In the event of recurrence of ANC < 1.0 x 109/l and/or platelets < 50 x 109/l, repeat step 1 and resume imatinib at reduced dose of 400 mg.
ANC = Absolute neutrophil count aOccurring after at least 1 month of treatment

Special populations
Paediatric population
There is no experience in children with CML below 2 years of age and with Ph+ALL below 1 year of age. There is very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.
The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less than 18 years of age have not been established in clinical trials.
Hepatic insufficiency
Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated.
Liver dysfunction classification:

Liver dysfunction	Liver function tests
Mild	Total bilirubin: = 1.5 ULN AST: > ULN (can be normal or < ULN if total bilirubin is > ULN)
Moderate	Total bilirubin: > 1.5 – 3.0 ULN AST: any
Severe	Total bilirubin: > 3 – 10 ULN AST: any

ULN = Upper limit of normal for the institution.
AST = Aspartate aminotransferase.
Renal insufficiency
Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy.
Older people
Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.

This information is for reference only. Please read the leaflet inside

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